The Clinical Genetics Branch (CGB) is NCI's base for intramural clinical cancer genetics translational research activity. CGB brings a multidisciplinary, epidemiologic perspective to: Understanding the role of genes in the cause, treatment, and prevention of cancer; Developing comprehensive management strategies for high-risk individuals and families; and Training the next generation of clinical cancer genetics investigators.Hereditary Breast/Ovarian Cancer (HBOC) is based on a prospective cohort of 33 BRCA mutation-positive families with extensive clinical/epidemiologic data and biological samples. Clinical activity related to this historic cohort has ended, but the biospecimens collected continue to be used in multiple translational research projects. To date, 17 clinical manuscripts have been published and 31 reports (in collaboration with the international consortium CIMBA) elucidating genetic modifiers of BRCA-related breast and ovarian cancer penetrance have been published. Inherited Bone Marrow Failure Syndromes (IBMFS) Study targets Fanconi anemia (FA) and related disorders with a predilection for aplastic anemia, myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and selected solid tumors. This is the first epidemiologically-grounded, etiologically-focused investigation of these rare disorders. We enrolled 1610 members from 374 families. Major findings include quantitative estimates of FA- and dyskeratosis congenita (DC)-related cancer risks, identifying the striking similarity in cancer risks in these 2 disorders, expanding the clinical phenotype of these disorders, and identifying very short telomeres as pathognomonic for DC. Under a grant from the Fanconi Anemia Research Foundation, we are studying immune function in FA patients. We have collaboratively analyzed cancer risks in the the North American, German and Israeli FA cohorts, and reported similar data from the NCI cohort. We collaborated on development of an in vitro assay for pathogenicity of missense variants of unknown significance in FANCD1/BRCA2. We have analyzed the North American Diamond- Blackfan Registry (DBAR) and documented for the first time significant risks of cancer, particularly osteogenic sarcoma, in DBA. A closely-related project, Familial Testicular Cancer is an inadequately-studied familial cancer disorder being evaluated under 2 protocols, one accruing new multiple-case families, the other aimed at mapping and cloning new TGCT susceptibility genes. Through the former, we have enrolled 1140 consented members from 144 newly-ascertained families. This multidisciplinary, etiologically-oriented family study has found that testicular microlithiasis is more common than expected in TGCT kindred, recognized a possible new FTGCT syndrome characterized by renal and pituitary neoplasms, colonic polyps, lymphomas and lentigenes, and identified germline mutations in the PDE11A gene as a modifier of FTGCT risk. We were the second largest contributor to International Testicular Cancer Linkage Consortium, through which we published multiple analyses related to the FTGCT phenotype. That Consortium has ceased to function, but it yielded the key hypothesis that has catalyzed current research into testicular cancer genomics, i.e., that the underlying genetic model involves the combined effects of multiple common genetic variants, each of relatively weak effect. Twenty-six variants in 9 genomic regions (involving testicular embryology, fertility,KIT signaling, telomere biology) have now been implicated in the genetic pathogenesis of TGCT. We contributed to two new recent GWAS analyses which identified 5 of the implicated genomic regions. BRThe Li-Fraumeni Syndrome (LFS), originally identified by DCEG investigators 40 years ago is a rare, inherited disorder caused by germline TP53 mutations, with increased risks of early-onset bone and soft tissue sarcomas, breast, adrenal and brain cancer. After a long hiatus, we have initiated a new LFSstudy which will conduct comprehensive clinical evaluations, provide genetic counseling and testing, investigate cancer screening modalities, identify genetic modifiers, study cancer risk-reduction strategies, and search for the genetic etiology in the 30% of affected patients without a TP53 mutation. An international workshop was held in November 2010 and resulted in formation of a new international LFS research consortium and the first LFS patient advocacy group. Familial Pleuropulmonary Blastoma (PPB) is a newly-described syndrome caused by germline mutations in DICER1; it represents the first known cancer predisposition syndrome caused by altered microRNA biogenesis. Leveraging an NIH Bench-to-Bedside award, we have formed a collaboration with the research group which made this remarkable observation, as a means to engage in the cutting-edge domain of miRNA research and introduce this technology into DCEG's research armamentarium. We will focus on more precisely defining the clinical phenotype of this remarkable disorder, in a new project that has just been submitted for IRB review. Neurofibromatosis 1 is a classic hereditary cancer susceptibility disorder. We are further defining its phenotype and seeking genetic modifiers of NF1 penetrance. Genetic Counseling, Psychosocial and Behavioral Studies in Familial Cancer is a vital component of CGB's research portfolio, which has yielded nearly 50 peer-reviewed publications. A series of projects are actively underway as part of each familial cancer study being conducted by the Branch. We are developing new genetic counseling tools (e.g., the Colored Ecogenetics Relationship Map), applying novel analytic strategies, such as social network analysis, analyzing the variables associated with choosing surgery or screening in GOG-199, assessing determinants of bone marrow transplant decision-making within FA families, and exploring the impact of ambiguous screening test results on mood and screening behavior of BRCA1/2 mutation carriers.g., the Colored Ecogenetics Relationship Map), applying novel analytic strategies, such as social network analysis, analyzing the variables associated with choosing surgery or screening in GOG-199, assessing determinants of bone marrow transplant decision-making within FA families, and exploring the impact of ambiguous screening test results on mood and screening behavior of BRCA1/2 mutation carriers.